Antisense insulin-like growth factor binding protein (IGFBP)-2-oligodeoxynucleotides for prostate and other endocrine tumor therapy

ABSTRACT

Compositions and a method are provided for the treatment of prostate and other endocrine tumors in mammals, including humans, by administration of an antisense oligodeoxynucleotide (ODN) which is complementary to a portion of the gene encoding IGFBP-2. Using the Shionogi tumor model in vitro and in vivo, the administration of such an ODN was shown to reduce proliferation of tumor cells, and also to delay the progression to androgen independence. Thus, treatment of prostate and other hormone-regulated cancer in mammals, including humans, and delay of the progression of prostate tumors to androgen independence is accomplished by administering to the mammal a therapeutically effective amount of an antisense oligodeoxynucleotide which is complementary to a portion of the nucleic acid sequence encoding IGFBP-2 and which reduces the amount of IGFBP-2 in the treated cells.

This application is a Section 371 national stage of PCT/US01/28748 whichclaims the benefit of U.S. Provisional Application 60/232,641 filed Sep.14, 2000.

FIELD OF THE INVENTION

The present invention relates generally to antisense oligonucleotidetherapy for cancer. More specifically, prostate and breast cancer aretargeted.

BACKGROUND OF THE INVENTION

This application relates to the treatment of prostate tumors making useof an antisense oligonucleotide that has a sequence complementary to thesequence encoding insulin-like growth factor binding protein (IGFBP)-2.

Prostate cancer is the most common cancer that affects men, and thesecond leading cause of cancer death in men in the Western world.Because prostate cancer is an androgen-sensitive tumor, androgenwithdrawal, for example via castration, is utilized in some therapeuticregimens for patients with advanced prostate cancer. Androgen withdrawalleads to extensive apoptosis in the prostate tumor, and hence to aregression of the disease. However, castration-induced apoptosis is notcomplete, and a progression of surviving tumor cells toandrogen-independence ultimately occurs. This progression is the mainobstacle to improving survival and quality of life, and efforts havetherefore been made to target androgen-independent cells. These effortshave focused on non-hormonal therapies targeted againstandrogen-independent tumor cells; however, no non-hormonal agent hasimproved survival thus far (Oh et al., J. Urol 160: 1220–1229 (1998)).Alternative approaches are therefore indicated. Recent studies in ourlaboratory suggest that increased levels of IGFBP-5 (Miyake et al,Endocrinology 141:2257–2265, (2000)) and IGFBP-2 after androgen ablationenhance IGF-1 mitogenesis and cell survival, thereby acceleratingprogression to androgen ablation.

Insulin-like growth factor (IGF)-I and IGF-II are potent mitogens formany normal and malignant cells. Accumulating evidence suggests thatIGFs play an important role in the pathophysiology of prostatic diseaseand breast cancer (Boudon et al., J. Clin. Endocrin. Metab. 81: 612–617(1996); Angelloz-Nicoud et al., Endocrinology 136: 5485–5492 (1995);Nickerson et al., Endocrinology 139: 807–810 (1998); Figueroa et al., J.Urol. 159: 1379–1383 (1998)).

The biological response to IGF's is regulated by various factors,including IGFBPs. To date, six IGFBPs have been identified whosefunction is believed to involve modulation of the biological actions ofthe IGFs through high affinity interactions (Rajaram et al. Endocrin.Rev. 18: 801–813 (1997)). However, some evidence suggests biologicalactivity for IGFBPs that are independent of IGPs (Andress et al., J.Biol. Chem. 267: 22467–22472 (1992); Oh et al., J. Biol. Chem. 268:14964–14971 (1993)), and both stimulatory and inhibitory effects ofIGFBPs on cell proliferation have been reported under variousexperimental conditions (Andress et al., supra; Elgin et al., Proc.Nat'l. Acad. Sci. (USA), 84: 3254–3258 (1987); Huynh et al., J. Biol.Chem. 271: 1016–1021 (1996); Damon et al., Endocrinology 139: 3456–3464(1998)). Thus, the precise function of IGFBPs remains controversial.Because of this, while the reported results implicate IGF in prostatecancer, they do not clearly suggest a therapeutic approach based uponthis involvement.

The present invention utilizes antisense oligodeoxynucleotides (ODNs)targeted to IGFBP-2 as a treatment for prostate and other endocrinecancers. Antisense ODNs are stretches of single-stranded DNA that arecomplementary to mRNA regions of a target gene, and thereby effectivelyinhibit gene expression by forming RNA/DNA duplexes (Figueroa et al., J.Urol., 159: 1379–1383 (1998)). Phosphorothioate ODNs are stabilized toresist nuclease digestion by substituting one of the nonbridgingphosphoryl oxygens of DNA with a sulfur. Recently, several antisenseODNs specifically targeted against genes involved in neoplasticprogression have been evaluated both in vitro and in vivo, anddemonstrated the efficacy of antisense strategy as potential therapeuticagents (Monia et al., Nature Med. 2: 668–675 (1996); Cucco et al.,Cancer Res. 56: 4332–4337 (1996); Ziegler et al., J. Natl. Cancer Inst.89: 1027–1036 (1997); Jansen et al., Nature Med. 4: 232–234 (1998)).

SUMMARY OF THE INVENTION

In accordance with the invention, compositions and a method are providedfor the treatment of prostate and other endocrine tumors in mammals,including humans, by administration of an antisense oligodeoxynucleotide(ODN) which is complementary to a portion of the gene encoding IGFBP-2.Using the androgen-sensitive human prostate cancer LNCaP andandrogen-dependent murine Shionogi tumor model in vitro and in vivo, theadministration of such an ODN was shown to reduce proliferation of tumorcells, and also to delay the progression to androgen independence. Thus,treatment of prostate cancer and other hormone-regulated cancers inmammals, including humans, and delay of the progression of prostatetumors to androgen independence is accomplished by administering to themammal a therapeutically effective amount of an antisenseoligodeoxynucleotide which is complementary to a portion of the nucleicacid sequence encoding IGFBP-2 and which results in a reduction ofIGFBP-2 levels in the target cancer cells.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows densitometry traces for Northern analysis demonstratingincreased IGFBP-2 mRNA levels in LNCaP cells after castration and duringandrogen-independent progression;

FIG. 2 depicts in vitro levels of viable human prostate LNCaP cellsshowing dose-dependent decreases in cell number after antisense IGFBP-2treatment;

FIGS. 3 a and 3 b show that treatment of LNCaP-tumor bearing mice aftercastration with IGFBP-2 ASO's reduces tumor growth rates and rises inserum PSA and delays time to androgen independent progression; and

FIG. 4 shows that treatment of human LNCaP tumor cells with IGFBP-2ASO's resulted in greater than 50% growth inhibition in a time- anddose-dependent manner.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for delaying the progression ofprostatic tumor cells to androgen independence, a therapeutic method forthe treatment of individuals, including humans, suffering fromhormone-regulated cancer such as prostate or breast cancer, andtherapeutic agents effective for use in such methods. In addition, thecompositions of the invention can be used to inhibit or delay the growthand metastatic progression of such cancers. The therapeutic method ofthe invention will most commonly be used in the treatment of individualswith advanced prostate cancer, but may also be used in conjunction withhormonal therapies of other endocrine malignancies, such as breastcancer.

In accordance with the first embodiment of the invention, theprogression of androgen-sensitive prostatic cancer cells to androgenindependence can be delayed by reducing the amount of IGFBP-2 in thecells. Experiments were performed in vitro and in vivo in theandrogen-sensitive human prostate cancer LNCaP and androgen-dependentmurine Shionogi tumor models. The Shionogi tumor model is a xenograft ofan androgen dependent mouse mammary carcinoma that grows subcutaneouslyin male syngeneic hosts. Shionogi tumor cells are highly tumorigenic andlocally invasive. The cells have been shown to respond to androgenwithdrawal in a manner which mimics the observed behavior of prostatictumor cells, and have been accepted as a valid model for prostate cancerin humans (Bruchovsky et al., Cancer Res. 50: 2275–2282 (1990); Rennieet al., Cancer Res. 48: 6309–6312 (1988); Bruchovsky et al., Cell 13:272–280 (1978); Gleave et al., in Genitourinary Oncology, pp. 367–378,Lange et al. eds., Lippencott (1997); Gleave et al., J. Urol. 157:1727–1730 (1997); Bruchovsky et al., The Prostate 6: 13–21 (1996)).Thus, androgen withdrawal precipitates apoptosis and tumor regression ina highly reproducible manner. Further, changes in expression andpeptides such as TRPM-2 and Bcl-2 in human prostate cancer followingcastration and during progression to androgen-independence are similarto those observed in Shionogi tumor cells. Because of thesesimilarities, the Shionogi tumor model mimics human prostate cancer andprovides a very useful model for the evaluation of the ability ofcompounds to delay the onset of androgen-independence. Despite completetumor regression after castration, rapidly growing androgen-independentShionogi tumors invariably recur after one month, which provides areliable end point to evaluate agents which can delay the progression toandrogen-independence.

In the study leading to the present invention, we initiallycharacterized the changes of IGFBP expression in the Shionogi tumormodel after castration and during AI progression. Northern blot analyseswere used to characterize changes in IGFBP mRNA expression in AD intacttumors before castration, regressing tumors 4 and 7 days aftercastration, and AI recurrent tumors 28 days after castration. Variouspatterns of changes in IGFBP-2, -3, -4, and -5 mRNA expression wereobserved. IGFBP-1 and IGFBP-6 mRNAs are undetectable in the Shionogitumor model.

Northern blotting was used to characterize changes in IGFBP-2 mRNAexpression in AD intact LNCaP tumors before castration and at varioustime points after castration. As shown in FIG. 1, IGFBP-2 expressionincreased gradually beginning 14 days after castration, and by 28 daysafter castration was >2-fold compared to levels before castration(two-sided p<0.05, student's t). Increased IGFBP-2 levels aftercastration was also identified using LNCAP and human prostate cancertumor tissue microarrays. Mean IGFBP-2 staining intensity increased from+1 in AD tumors (n=20 spots) before castration to +2.3 in AI tumors(n=40 spots, 28 and 35 days after castration). The mean intensities ofother groups were +1 for 3 days, +1.2 for 5, 7 and 10 days, +1.4 for 14days, and +1.6 for 21 days after castration. Immunohistochemicalstaining results generally corresponded with results from Northernblotting.

In accordance with the present invention, antisense ODN's which arecomplementary to the sequence encoding IGFBP-2 are administered. Whenthe subject is human, the sequence administered is based on humanIGFBP-2. Specific antisense ODN are listed in Table 2 and are identifiedas Seq. ID Nos. 1–56. Seq. ID. No. 1 which includes the translationinitiation site was the most active of those tested, and was used in themajority of the experiments reported herein. The ODNs employed maybemodified to increase the stability of the ODN in vivo. For example, theODNs may be employed as phosphorothioate derivatives (replacement of anon-bridging phosphoryl oxygen atom with a sulfur atom) which haveincreased resistance to nuclease digestion. Increased ODN stability canalso be achieved using molecules with 2-methoxyethyl substitutedbackbones.

Administration of antisense ODNs can be carried out using the variousmechanisms known in the art, including naked administration andadministration in pharmaceutically acceptable carriers. For example,lipid carriers for antisense delivery are described in U.S. Pat. Nos.5,855,911 and 5,417,978 which are incorporated herein by reference. Ingeneral, the antisense is administered by intravenous, intraperitoneal,subcutaneous or oral routes.

The amount of antisense ODN administered is one effective to reduce thelevels of IGFBP-2 in prostatic cells or other hormone-regulated tumorcells. In the context of the present invention, applicants do not intendto be bound by any specific mechanism by which this reduction may occur,although it is noted that the reduction may occur as a result of reducedexpression of IGFBP-2 if the antisense molecule interferes withtranslation of the mRNA, or via an RNase mediated mechanism.Furthermore, it will be appreciated that the appropriate therapeuticamount will vary both with the effectiveness of the specific antisenseODN employed, and with the nature of any carrier used. The determinationof appropriate amounts for any given composition is within the skill inthe art, through standard series of tests designed to assess appropriatetherapeutic levels.

The method for treating prostate cancer in accordance with the inventionmay further include administration of chemotherapy agents and/oradditional antisense ODNs directed at different targets. For example,conventional chemotherapy agents such as taxol (paclitaxel or docetaxel)and mitoxanthrone may be used. Similarly, combinations of antisenseIGFBP-2 ODN with other antisense sequences such as antisense Bcl-2 ODN,TRPM-2 ODN, or IGFBP-5 ODN may be used.

EXAMPLES

The invention will now be further described with reference to thefollowing, non-limiting examples.

Example 1

Three oligonucleotides were prepared with the sequences given in Seq.ID. Nos. 1–3. Seq. ID No. 1 spans the translation initiation site of theIGFBP-2 mRNA starting with base number 64. Seq. ID Nos. 2 and 3correspond to bases 131–151 and 630–650 respectively. Two base IGFBP-2mismatch oligonucleotides (Seq. ID Nos. 57–59) were also prepared ascontrols.

Initial screening on these three oligonucleotides was done using LNCAPcells. Lipofectin, a cationic lipid (Life Technologies Inc.Gaithersburg, Md.) was used to increase uptake of the oligonucleotidesinto the cells. LNCaP cells were treated with one of the threeoligonucleotides (Seq. ID. Nos. 1–3), 1000 nM, or the correspondingmismatch control (Seq. ID Nos. 57–59). Total RNA was extracted andanalyzed by Northern Blot analysis for levels of IGFBP-2 encoding RNA.Glyceraldehyde-3-phosphate dehydrogenase (G3PDH) was used as a control.The probes used had the sequences given by Seq. ID. Nos. 60–63. The RNAblots were hybridized with human IGFBP_(—)2 probe labeled with [³²P]dCTPby random primer labeling. Washing and densitometric analysis wascarried out. After detecting the IGFBP-2 encoding RNA, the membraneswere re-probed using human G3PDH probes to verify integrity.

Seq. ID No. 1 was most effective, causing up to 80–90% reduction inIGFBP-2 mRNA levels. Seq ID. Nos. 2 and 3 were also effective, albeitless so, causing a decrease of about 50%.

Example 2

The LNCaP model is an androgen-sensitive, PSA-secreting, human prostatecancer cell line that can be induced to form tumors in athymic miceunder a variety of conditions. Like in human prostate cancer, serum PSAlevels in this model are regulated by androgen and are directlyproportional to tumor volume. After castration, serum and tumor-cell PSAlevels decrease up to 80% and remain suppressed for 3–4 weeks. Beginning4 weeks after castration, however, PSA production gradually increasesabove pre-castrate levels in the absence of testicular androgens,heralding the onset of androgen-independent progression. The pattern ofchanges in gene expression after castration in the LNCaP model issimilar to that in the Shionogi system, with increased expression ofBcl-2, TRPM-2, and IGFBP-2 following castration of mice bearing LNCaPtumors. It is important to stress that many of the changes in geneexpression in the LNCaP and Shionogi models also occur in human prostatecancer (e.g, Bcl-2, clusterin, IGFBP's, PSA, Bcl-xL), which validatestheir use as models of the human disease for functional genomics andpreclinical proof of principle experiments. In the study leading to thepresent invention, we initially characterized changes of IGFBPexpression in the LNCaP tumor model after castration and during AIprogression. Northern blot analyses showed that IGFBP-2 levels increasedup to 2–3 fold in androgen-independent tumors compared to androgendependent tumors prior to castration, suggesting IGFBP-2 increases maybe associated with the development of the androgen-independent phenotype(FIG. 1).

Example 3

The Shionogi tumor model mimics human prostate cancer and provides avery useful model for the evaluation of the ability of compounds todelay the onset of androgen-independence. Despite complete tumorregression after castration, rapidly growing androgen-independentShionogi tumors invariably recur after one month, which provides areliable end point to evaluate agents which can delay the progression toandrogen-independence. In the study leading to the present invention, weinitially characterized changes of IGFBP expression in the Shionogitumor model after castration and during AI progression. Northern blotanalyses were used to characterize changes in IGFBP mRNA expression inAD intact tumors before castration, regressing tumors 4 and 7 days aftercastration, and AI recurrent tumors 28 days after castration. IGFBP-2levels increased up to 2–3 fold in androgen-independent tumors comparedto androgen dependent tumors prior to castration, suggesting IGFBP-2increases may be associated with the development of theandrogen-independent phenotype.

Example 4

Treatment of human LNCaP cells with IGFBP-2 ASO (Seq. ID. No. 1)resulted in dose-dependent and sequence-specific downregulation ofIGFBP-2 mRNA and protein levels. IGFBP-2 levels were decreased by 90%after treatment with 500 nM IGFBP-2 ASO (Seq. ID. No. 1). Cell viabilityalso decreased in a dose-dependent manner. (FIG. 2).

Example 5

Treatment of human LNCaP tumor cells with IGFBP-2 ASO (Seq. ID. No. 1)decreased target mRNA and protein levels greater than 90% and resultedin greater than 50% growth inhibition in a time- and dose-dependentmanner (FIG. 2).

Example 6

Systemic administration of IGFBP-2 ASO (Seq. ID. No. 1) in mice bearinghuman LNCaP prostate tumors after castration significantly delayed thegrowth of AI recurrent tumors and time to sacrifice. LNCaP tumor growthand rises in serum PSA were both significantly delayed in mice treatedwith IGFBP-2 ASO's compared to controls treated with mismatch ASO's(FIGS. 3 a and 3 b). These findings provide the first evidence thatupregulation of IGFBP-2 after castration enhances the mitogenic activityof IGF-I, and illustrates a potential use for IGFBP-2 ASO therapy forprostate cancer.

Example 7

Treatment of human LNCaP tumor cells with IGFBP-2 ASO (Seq. ID. No. 1)decreased target mRNA and protein levels greater than 90% and resultedin greater than 50% growth inhibition in a time- and dose-dependentmanner, an effect that could not be reversed by exogenous IGF-I (FIG.4). IGFBP-2 ASO (Seq. ID. No. 1) plus IGF-I antibody treatment hadadditional inhibitory effect on LNCaP tumor cell growth in vitro.

Example 8

To examine the effects on cell cycle regulation of decreases in IGFBP-2levels by IGFBP-2 ASO treatment, changes in cyclin D1 levels wereevaluated in LNCaP cells after treatment with IGFBP-2 ASO (Seq. ID. No.1). Western analysis demonstrated a greater than 50% decrease in cyclinD1 after IGFBP-2 ASO (Seq. ID. No. 1) treatment, illustrating thatdecreases in IGFBP-2 by ASO treatment inhibits IGF-I signaling andresults in cell cycle arrest. Apoptosis induction after IGFBP ASOtreatment was also shown by LNCaP cell cycle analysis by flow cytometryafter treatment with IGFBP-2 ASO. LNCaP cells were treated daily withIGFBP-2 ASO or mismatch control oligonucleotide with or without 1 nM DHT(dihydrotestoterone) for 2 days. Table 1 shows cell populations in eachphase (Sub G1−G0, G1−G0, S, and G2+M) in % for the various treatments.Each datum represents the mean value of triplicate experiments. AfterIGFBP-2 ASO treatment, the percent of cells in Sub G1−G0 increased3-fold (p<0.05), while percent of cells in G2+M decreased by 50%.

TABLE 1 Treatment Sub G1-G0 G1-G0 S G2 and M No TX DHT 8.5 82 4.2 5 (+)IGFBP-2 ASO 28 65.4 2.9 3.8 DHT (+) MM control 9.5 81.6 4.4 5.8 DHT (+)No TX DHT (−) 7.9 79.1 4.5 8.6 IGFBP-2 ASO 24.6 68.8 2 4.6 DHT (−) MMcontrol 9 79.4 3.5 8.2 DHT (−)

Example 9

Metastatic prostate and breast cancer frequently invade bony tissue.Treatment of such metastases is very difficult, and progression of thecancer into the bone generally indicates a poor prognosis for long termsurvival. Thus, it would be desirable to have a methodology forinhibiting or delaying this progression. It was logical to assume thatsince IGF-I and IGFBP-2 are important factors for growth of IGF-Isensitive cancer, including in particular prostate and breast cancer,that the presence of high levels of IGFBP-2 in bone could be animportant mechanism for promoting the growth and progression ofmetastatic lesions. Accordingly, Western analysis was performed onsamples of primary human bone tissue cultures. This experiment confirmedthe presence of high levels of IGFBP-2 in bone. inhibition of theselevels using antisense IGFBP-2 ODN in accordance with the inventionshould provide an effective therapy for inhibiting or delaying theprogression of metastatic lesions in the bone.

TABLE 2 Seq. ID No. 1 GCAGCCCACTCTCGGCAGCAT Seq. ID No. 2CGCCCAGTAGCAGCAGCAGCA Seq. ID No. 3 TCCCGGAACACGGCCAGCTCC Seq. ID No. 4CAGCCCACTCTCGGCAGCAT Seq. ID No. 5 GGGCAGCGGAACAGCACCTC Seq. ID No. 6CCCGGCTCCCGGACGAGCTC Seq. ID No. 7 GCCTGCAGGGGCAGCTCGGA Seq. ID No. 8ACGTGGTTCTCCACCAGGCC Seq. ID No. 9 CCCATCTGCCGGTGCTGCTC Seq. ID No. 10AGGCGCATGGTGGAGATCCG Seq. ID No. 11 CACTCCCCACGCTGCCCGTT Seq. ID No. 12CGCTGGGTGTGCACCCCGCG Seq. ID No. 13 TGTCAGAACTGGAAAATCCT Seq. ID No. 14GCAGCCCACTCTCGGCAGCAT Seq. ID No. 15 CAGTAGCAGCAGCAGCAGCGG Seq. ID No.16 TGTGCAGGGCGGGCAGCGGAA Seq. ID No. 17 GCCCTCCACCGGGGCGCACAC Seq. IDNo. 18 GCCCGGGTGGGGATAGCAGCG Seq. ID No. 19 CGCCTGCAGGGGCAGCTCGGA Seq.ID No. 20 AGTGCCCTCGCCCATGACCAG Seq. ID No. 21 CTCCGGGCTGGCGCCATACTCSeq. ID No. 22 ATCGCCATTGTCTGCAACCTG Seq. ID No. 23CAGGCCTCCTTCTGAGTGGTC Seq. ID No. 24 GCTGTCCACGTGGTTCTCCAC Seq. ID No.25 CCCGCCCAACATGTTCATGGT Seq. ID No. 26 CTTCCGGCCAGCACTGCCTCC Seq. IDNo. 27 CTTCATACCCGACTTGAGGGG Seq. ID No. 28 CTCCCGGAACACGGCCAGCTC Seq.ID No. 29 CCGGTGCTGCTCAGTGACCTT Seq. ID No. 30 CTTGCCACCCTTGCCCATCTGSeq. ID No. 31 CTCCTCCAGGCCAAGGTGATG Seq. ID No. 32GGGTGGTCGCAGCTTCTTGGG Seq. ID No. 33 TTGGCAGGGAGTCCTGGCAGG Seq. ID No.34 CAGGACCTGGTCCAGTTCCTG Seq. ID No. 35 GCGCATGGTGGAGATCCGCTC Seq. IDNo. 36 AGGGCCCCGCTCATCCGGAAG Seq. ID No. 37 CAGGGAGTAGAGGTGCTCCAG Seq.ID No. 38 CTTGTCACAGTTGGGGATGTG Seq. ID No. 39 TTTGAGGTTGTACAGGCCATGSeq. ID No. 40 GTTCAGAGACATCTTGCACTG Seq. ID No. 41CCAGCACTCCCCACGCTGCCC Seq. ID No. 42 CCCGGTGTTGGGGTTCACACA Seq. ID No.43 GGGGGCTCCCTGGATCAGCTT Seq. ID No. 44 CTCGGGGTCCCCCCGGATGGT Seq. IDNo. 45 CTCATTGTAGAAGAGATGACA Seq. ID No. 46 CGCCCAGTAGCAGCAGCAGCA Seq.ID No. 47 TCCCGGAACACGGCCAGCTCC Seq. ID No. 48 CAGCCCACTCTCGGCAGCAT Seq.ID No. 49 GGGCAGCGGAACAGCACCTC Seq. ID No. 50 CCCGGCTCCCGGACGAGCTC Seq.ID No. 51 ACGTGGTTCTCCACCAGGCC Seq. ID No. 52 CCCATCTGCCGGTGCTGCTC Seq.ID No. 53 AGGCGCATGGTGGAGATCCG Seq. ID No. 54 CACTCCCCACGCTGCCCGTT Seq.ID No. 55 CGCTGGGTGTGCACCCCGCG Seq. ID No. 56 TGTCAGAACTGGAAAATCCT Seq.ID No. 57 GCAGCCCACTGTCCGCAGCAT Seq. ID No. 58 CGCGCACTAGCAGCAGCAGCASeq. ID No. 59 TCCCGGAACTGCCCCAGCTCC Seq. ID No. 60ACAATGGCGGATGACCACTCAGA Seq. ID No. 61 ACAGCACCATGAACATGTTTG Seq. ID No.62 TGCTTTTAACTCTGGTAAAGT Seq. ID No. 63 ATATTTGGCAGGTTTTTCTAGA

1. A method for treating a hormone-responsive cancer in an individualsuffering from hormone-responsive cancer, comprising administering tothe individual a composition comprising an antisense oligonucleotidewhich targets IGFBP-2 and thereby inhibits expression of IGFBP-2 byhormone-regulated tumor cells, whereby growth and metastatic progressionof the cancer is inhibited or delayed in the individual.
 2. The methodof claim 1, wherein the composition is administered to the individualafter initiation of hormone-withdrawal to induce apoptotic cell death ofhormone-responsive cancer cells in the individual, and thereby delaysthe progression of hormone-responsive cancer cells to ahormone-independent state in the individual.
 3. A method for delayingprogression of hormone-regulated tumor cells to an hormone-independentstate comprising the step of treating hormone-sensitive tumor cells withan antisense oligonucleotide which targets IGFBP-2 and thereby inhibitsexpression of IGFBP-2 by the tumor cells, whereby progression of thetumor cells to androgen independence is delayed.
 4. The method of claim1 wherein the individual is a human.
 5. The method of claim 1 whereinthe cancer treated is prostate cancer and the tumor cells are prostatictumor cells.
 6. The method of claim 1 wherein the cancer treated isbreast cancer and the tumor cells are breast cancer cells.
 7. The methodof claim 5, wherein the individual is human.
 8. The method of claim 6,wherein the individual is human.